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“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact” ~ Charles Darwin (it's evolutionary baybeee!)

Sunday, October 22, 2017

β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-β-cell relationships

BUMP NOTICE:

I'm bumping this post due to some recent discussions on social media regarding the reversibility of Type 2 Diabetes and the role of low carbohydrate diets in the growing "curing diabetes" paradigm. Recently Dr. Roy Taylor (the investigator I most closely associate with the crash diet, though this is an extensive group) and colleagues, who implemented a "crash diet" to cure diabetes -- by reducing pancreatic and hepatic (liver) fat concurrently with rapid weight loss -- published the following in BMJ: Beating type 2 diabetes into remission. The criteria are non-diabetic markers for a period following reversal of the progression. Here is where various low carbohydrate interventions "fail", as many are able to maintain normoglycemia only by avoiding carbohydrates. The question remains if this is effectively the same as other reversals. I contend it is not, as normal pancreatic function -- specifically GSIS -- has not been restored. Anecdotally (because we really don't have truly long term studies on LCHF following weight loss phase), many LCHFers see rising fasting levels, and one outspoken advocate, Tim Noakes, is among the many who remain on metformin to manage glucose levels. The burning question, that remains unstudied by the advocates of low carbohydrate diets, is whether such diets will slow, halt or reverse the disease itself. Here is where rodent data is NOT promising, especially when diabetes is viewed across the full metabolic milieu rather than the isolated metric of blood glucose.

Yes, this is a rat study, but it seems applicable in light of the recent Diabetes "Crash Diet" Cure and the reductions in pancreatic fat seen in the study. The study and the pancreatic fat issue were discussed here. Summary: 11 diabetics followed a 600 cal/day diet for 8 weeks and regained normal insulin secretion and glycemic control. The restored glucose induced insulin secretion (GSIS) was attributed to reduction in pancreatic fat content.

The investigators in the current study had this to say in the introduction (bolded emphasis is mine):

Long-chain fatty acids, which may be central to the development of insulin resistance in NIDDM, can stimulate basal insulin secretion and inhibit GSIS in isolated islets. This suggests a scheme that could account for the β-cell abnormalities in pre-NIDDM and NIDDM and explain the relationship between insulin resistance and β-cell dysfunction. In this model the increase in plasma free fatty acids (FFAs) associated with prediabetic obesity causes both the insulin resistance and the matching hyperinsulinemia of the prediabetic state; subsequently a further increase in FFAs causes the β-cell unresponsiveness hyperglycemia that characterizes overt diabetes.

The present study tests this hypothesis in a rodent model of obesity-associated NIDDM that most closely resembles the human disorder, the Zucker diabetic fatty (ZDF-drt) rat. NIDDM begins in almost 100% of obese male ZDF rats (fa/fa) between 7 and 10 weeks of age, while virtually all obese female ZDF rats (fa/fa) remain nondiabetic. This permits early identification of prediabetic and nonprediabetic littermates. It is, therefore, possible to test the propositions that the hyperinsulinemia of the compensated prediabetic phase results, at least in part, from a moderate rise in plasma FFA levels and that the later loss of GSIS is caused by a further increase in FFAs to a critical concentration that blocks the β-cell response to glucose.

In parts of this study I'll discuss include three groups of rats:

obese male ZDF prediabetic and diabetic rats (fa/fa)

obese female ZDF nondiabetic rats (fa/fa)

nonobese male ZDF littermates (fa/+ or +/+)

male Wistar rats.

{Note: This study also involved some in vitro experiments involving culturing islets in various media. I will address these in a future blog post as time permits. However feel free to comment on them if there's something there of interest to you.}

The researchers bred the ZDF rats that are genetically predisposed to obesity (by 4 weeks) and all males of this strain become diabetic by 8-10 weeks. At 6 weeks the male ZDF rats are considered prediabetic. The females of the strain develop hyperinsulinemia and hyperlipidemia but do not develop hyperglycemia. All rats were fed the same chow.

To test their hypothesis:

The validity of the [our] hypothesis ... requires that significant hyperlipacidemia be present in prediabetic rats prior to the appearance of hyperglycemia. We therefore obtained weekly measurements of free FFAs and TGs in the plasma of obese male ZDF prediabetic rats, using female homozygotes and male heterozygotes as obese and nonobese controls. Sampling began at 5 weeks of age-i.e., 3-4 weeks before the onset of overt diabetes-and continued until 14 weeks of age, at which time overt diabetes had been present for at least 4 weeks.

Here are the results: (Please note quotes from the paper have certain statistical values and citations removed for ease of reading, as I find this "clutter" distracting.)

... the most striking finding was in the prediabetic males; at 7 weeks of age, 2 weeks before the appearance of hyperglycemia, their mean FFA level had risen to 1.2 ± 0.05 mM, significantly greater than in the obese and lean controls, and was 1.9 + 0.06 mM at 10 weeks of age, several days after the onset of hyperglycemia. Thus, islets of prediabetic rats were exposed to higher plasma FFA levels than their obese and lean littermates for an average of 2 weeks before the onset of hyperglycemia.

There was a significant correlation between the morning blood glucose levels and the plasma levels of FFAs of Fig. 1 at the onset of overt NIDDM plasma FFAs exceeded 1.5 mM in every rat.

💥EDIT: What the above boils down to is evidence that the rise in NEFA precedes the development of frank diabetes as determined by the "end line" symptom of hyperglycemia.💥

In addition to triglyceride content, they measured other functions of the islets themselves including both basal and glucose stimulated insulin production, and GLUT-2 transporter activity. GLUT-2 is the "sensor" or mediator of GSIS in the β-cell.

We reasoned that if fatty acyl CoA in islets increases in proportion to the plasma levels of FFAs, in the presence of sufficient glycerol 3-phosphate for reesterification of the fatty acids, secondary TG formation might take place in the islets. A reduction in β-cell glycerol-3-phosphate shuttle activity, which has been reported in two other animal models of NIDDM, would increase glycerol 3-phosphate, a requirement for TG synthesis. We therefore measured islet TG content. In islets of prediabetic ZDF rats, [they found]

TGs had increased 4-fold between the ages of 5 and 8.5 weeks.

An additional, abrupt 2-fold increase occurred by 9 weeks of age, when the mean glucose level had reached 10.6 mM.

At 10 weeks islet TG content reached a plateau that was 10 times higher than in 5-week-old prediabetic ZDF rats and 10-week-old lean littermates

There was a significant correlation between plasma FFA and islet TG levels consistent with reesterification of fatty acids in islets. Islet TG content was also correlated with blood glucose levels.

Next, the researchers further tested their hypothesis by pair feeding (e.g. assessing ad libitum intake of lean controls and feeding the same diet/amount to the study group rats) the obesity/diabetes prone rats and lean littermates. They raised the rats as usual until 6 weeks (already obese by ~4 weeks) when the male ZDB rats became prediabetic. For the next 6 weeks they pair fed them - e.g. restricted calories - to see if it would prevent the β-cell impairment their ad libitum fed brethren exhibited. The result?

... the moderate reduction in plasma FFAs was associated with marked attenuation of the entire phenotype of NIDDM-i.e., the hyperglycemia, hypertriacylglycerolemia, accumulation of fat in islets, and loss of β-cell GLUT-2 glucose transporter. Basal hypernsulinemia was reduced by 60%, to below the levels of obese nondiabetic female ZDF controls, and GSIS was preserved at about half of the normal level in nondiabetic controls. The loss of GLUT-2 was prevented.

💥EDIT: In a nutshell, they were able to prevent a significant amount of the inevitable development of diabetes with calorie restriction.💥

So, not a complete prevention of diabetes, but a marked retarding of the progression of the disease. Some excerpts from the discussion (bold emphasis mine):

These results in a rodent model of obesity and insulin resistance provide evidence for a "lipotoxic" cause of some of the β-cell abnormalities observed before and after the onset of NIDDM. First, the onset of progressively increasing hyperlipacidemia, beginning ~2 weeks before the loss of GSIS and onset of hyperglycemia, provides ample time for the postulated changes in β-cells to occur; without exception the plasma FFA concentration exceeded 1.5 mM and islet TG content was greater than 0.7 μg per islet just before the onset of hyperglycemia, both values were significantly greater than those of either control group (Lipid droplets were detected in sections of diabetic islets.)

Second, a moderate reduction of the lipid abnormalities in obese prediabetic rats by means of caloric restriction reduced the β-cell abnormalities of NIDDM, although interpretation of this particular finding is complicated by the multiple consequences of dietary restriction. ...

... By invoking a relationship in which elevated FFA concentrations concomitantly induce insulin resistance in target tissues and insulin hypersecretion in β-cells, one can explain how insulin secretion manages to match the level of insulin resistance and prevent the development of hyperglycemia as obesity progresses. (It is not clear whether the very earliest stage of hyperinsulinemia is FFA-driven.) However, whenever FFA levels in prediabetic rats exceeded 1.5 mM, their β-cells apparently became incapable of a further increase in secretory function to parallel the rising insulin resistance; first-phase GSIS is abolished at this stage of the disease and hyperglycemia appears.

The results suggest that obesity-related NIDDM is characterized by two defects:

(i) a primary resistance in adipocytes to the antilipolytic effects of insulin in obese animals, which causes the hyperlipacidemia that, in turn, induces insulin resistance in muscle and insulin hypersecretion and

(ii) impairment in the β-cell response to glucose.

It remains to be shown that these findings in ZDF rats are relevant to insulin resistance and NIDDM in humans.

That last caveat is, of course, important to keep in mind when extrapolating the results of genetic model rodent studies to humans. However, much research has been done on humans looking at, for example, the role of NEFA/FFA in basal hyperinsulinemia, etc.

This study demonstrated that only the rats that became diabetic experienced this rise in plasma NEFA that preceded the hyperglycemia. This is something I've blogged on for over a year now. I would note that this current paper is relatively old, 1994. From Bierman to McGarry to Boden to Frayn, the fingers of researchers who actually work with this stuff points to the NEFA as the critical primary condition in diabetes: hyperNEFAimea --> hyperglycemia.

This study also shows that there is obviously a genetic component to the disease. Some apparently retain adipocyte functioning better and/or have more resilient β-cells than others. In humans, obesity is almost always associated with elevated NEFA as larger adipocytes lose their insulin sensitivity. This seems to have the following impacts on circulating NEFA levels:

Increased basal levels due to adipocyte-IR and greater NEFA release

Increased post-prandial NEFA release do to failure of insulin-mediated suppression in the IR-adipocyte.

Increased post-prandial NEFA do to decreased "trapping" of dietary fatty acids released from chylomicrons by the IR-adipocyte (EDIT: I've seen increasing evidence that this may not be a significant contributor if at all.)

The major underlying theory of the carbohydrate/insulin hypothesis is that insulin is trapping your fat in your cells and causing fat accumulation. If this is to be believed, then reducing dietary carbohydrate would increase each contribution to circulating NEFA above. In caloric deficit, the significant increase in NEFA seems to be benign as we're burning the fatty acids for energy. In these early phases, there can be no doubt that the immediate improvements in postprandial hyperglycemia and need for insulin favor carbohydrate restriction. But as is pointed out time and again, once maintenance is reached, the VLC diet (and even a moderately LC diet for some) is necessarily a HF diet -- both by percentage and absolute intake. This can only serve to sustain the elevated NEFA levels that produced the diabetes in the first place. And this is why even Dr. Davis now acknowledges that his VLC diet has his diabetes in remission but not cured. There are, however, still people hanging their health on the hook that w/o carbs, fatty acids won't accumulate in your organs because of that G3P theory that just won't go away. Perhaps Mr. Gary Taubes could come out more forcefully on his blog with the mea culpa on that one. Yes, G3P is required, but just as gluconeogenesis creates what glucose we need, so too, glyceroneogenesis creates what G3P we need. And in the end, you want that, because it also seems somewhat protective -- for a while anyway -- for the NEFA/FFA to be re-esterified. The triglyceride content per se is not a problem at certain levels or when it is tapped into frequently (e.g. trained endurance athletes). Ectopic (non-adipose tissue) deposition of triglycerides may well be the body's last line of defense in the overfed state.

I believe that the diabesity epidemic has merely revealed that more of the human population is susceptible to developing diabetes than previously thought, and/or simply that more of the human population is reaching that critical level of obesity that sets the whole ball in motion. Still, a large percentage of the obese never progress to the point of loss of glycemic control. But if you've been diagnosed or are prediabetic, that recent "crash diet" study demonstrated that, in humans, there's something to this whole lipotoxicity thing after all, and that perhaps the dramatic calorie restriction has a more dramatic impact at "flushing" fat from the pancreas. The appearance of lipid droplets in the tissue sections in the current study lead credence to the theory that local fat accumulation in the pancreas may amplify the NEFA delivery to the β-cell. I don't see how any serious person can merely reject/ignore the tremendous body of research out there on this.

At maintenance, a LC/HF diet is going to increase NEFA, and more importantly mute the natural rise and fall throughout the day on a mixed diet. Will this be detrimental to all? Obviously not. Could it be detrimental to some? When statistically zero humans have ever consumed such a diet in the context of relative prosperity (e.g. cheap, fatty meat in abundance requiring almost no effort to procure), I think it's hard to make the case that this is an unimportant consideration in deciding that such an extreme diet won't be detrimental to those pre-disposed let alone optimal for all. On the other hand, we have billions of humans eating carbohydrate based diets in good health. The SAD is high in fat, carb and processed mixed foods. It clearly leads to obesity which leads to diabetes in those pre-disposed. To not progress from prediabetic -> diabetic, or to reverse early onset diabetes the solution is to lose weight. Reverse the obesity to a certain point and get those NEFA levels down to levels the pancreas can handle. But once you've done that, it would seem prudent to adopt a diet that will prevent NEFA from exceeding the threshold for β-cell demise.

If your diet only keeps glucose at levels below a glucotoxic threshold, you're only treating the symptom. If it also keeps NEFA levels below lipotoxic levels, now you are treating the disease itself.

A last comment on NEFA and dietary fat. Does dietary fat "cause" diabetes per se? No. Not if it is not contributing to the chronic excess energy intake that leads to obesity (or fat accumulation in excess of some individual threshold). But once a person reaches a certain metabolic state, dietary fat DOES contribute to NEFA levels when the adipocytes fail to adequately trap the fatty acids. This can do nothing but compound the problem when one is in a weight maintaining or gaining state. This is a bit of a shift in my thought process that was heavily influenced by Keith Frayn's recent Fatty Acid Trafficking paper dealing with post-prandial contributions to NEFA. A high fat, very low carb diet would only further mute the proper suppression of NEFA release in the post-prandial phase, and if you truly believe that fat deposition in fat cells is reduced by the low carb state, dietary fat can only serve to increase NEFA further.

28 comments:

This is a nice descriptive study, and one of the more convincing pieces of evidence I've seen in support of the FFA hypothesis of diabetes, although as they didn't manipulate FFA it can't establish causality.

The genetic defect in Zucker rats is that they lack the leptin receptor. I went to a talk by Christopher Buettner the other day where he presented evidence (published) that insulin's antilipolytic effects are mediated in large part through the brain. Leptin and insulin signaling are synergistic in the brain in some respects. I think that CNS effects are probably important in the FFA phenotype of Zucker rats.

I think it's interesting that the animals were presumably all on standard low-fat chow. Leptin signaling trumps diet composition when it comes to weight gain and diabetes!

It is unfortunate that NEFA are apparently rather difficult to measure because it's not a routine test. After everything I've read, I would be surprised were we not to see a similar pattern in those who develop diabetes were we, say, to do twice yearly measurements of several parameters in those (like offspring of diabetics) predisposed to develop the disease.

Clearly more than just the NEFA is at play here, there's some sort of additional susceptibility involved and/or turnover capability.

"I think it's interesting that the animals were presumably all on standard low-fat chow. Leptin signaling trumps diet composition when it comes to weight gain and diabetes!"

The leptin signaling causes these rats to overeat and become predictably obese. Has anyone ever pair-fed these rats with their lean littermates from birth to see if they even get obese?

This is both the drawback and utility of these genetic strains. They produce predictable results but the results do not translate even to normal rats. To fatten normal rats and make them diabetic, the low fat chow is unsuccessful, but that CAF diet worked well!

Shortly after Kurt made his ... erm ... let's just call them "contributions" to the discussion on lipotoxicity here on my blog, I came across this citation.

Are you familiar with the work of Dr. Edwin Bierman? It struck me as somewhat odd at the time that you would not be as he was a legend at the University of Washington which is where you received your PhD and the head of the DIVISION OF METABOLISM, ENDOCRINOLOGY AND NUTRITION is Alan Chait, M.D., Edwin L. Bierman Professor and Head

Bierman is the person responsible for the ADA's dietary recommendations in favor of higher carb intake. The keynote speech at the ADA is also named for him. A citation:http://www.ajcn.org/content/41/5/1113.long

It is very clear to me that diabetologists are well aware of NEFA and the potential lipotoxic effects. Does the diet's contribution to NEFA levels make a difference? Considering that the problem for T2's in this regard is failure to adequately suppress release from adipose tissue after a mixed meal (and it's been demonstrated this is worse after a high fat low carb meal) coupled with potential direct dietary NEFA that aren't trapped, I don't see how anyone can dismiss this sort of thing out of hand.

I can't put my finger on the specific study I blogged on, but a high fat low carb diet has been shown to hasten the progression of diabetes in rats prone to developing the disease. Peter did a hatchet job on Axen whom I believe was the author of that study, but the fact that his pet -- looks like a Sprague Dawley -- "Ratty" is doing fine on his high fat diet doesn't carry as much weight to me as Axen's work.

I'm quite familiar with the department of Metabolism, Endocrinology and Nutrition at UW because it's my department. I don't know Dr. Edwin Bierman because he no longer works here, but I suppose I should get acquainted with him.

Leptin signaling deficient animals can't be starved thin, even with drastic calorie restriction. They will experience lean mass atrophy and eventually die while remaining fat (although not as fat as ad lib fed controls). I agree with your caveats about using them as a model of obesity.

I agree that a failure to suppress FFA postprandially could be a major factor in diabetes, particularly because you get high glucose and high FFA at the same time, which is very bad.

But I'm still not convinced that the lack of postprandial suppression following a low-carb meal is problematic. The reason FFA are suppressed after a carb meal is because glucose is being prioritized as a metabolic fuel and it's bad to have them both around in high concentrations. But when there's no glucose spike, and you're still oxidizing FFA at the same rate as in the fasting state, why would you want to suppress FFA postprandially?

My feeling is that if you're going to overfeed, it's probably best to do it on carbohydrate, but that's because overfeeding on carb leads to less body fat gain. But I'm still not convinced it makes a difference when a person is eating an appropriate number of calories.

Hi Ned ... I have to look for which article it was I blogged on that had a whole TNF-alpha component to it -- or there was a "sister article". I believe these things are all interconnected for sure!

For me the lipotoxicity first makes sense b/c it doesn't seem that the body would attack itself without provocation. The excessive fatty acids and/or the cell death they elicit -> inflammatory response makes more sense to me. Obviously there are autoimmune things at play as well, but there seems to be enough info out there to indicate these are somewhat different pathologies entirely.

I'll take a closer look at your link, etc. when I get a chance. Thanks!

Here's a reference for the effects of starvation on leptin-deficient (ob/ob) mice:

http://www.ncbi.nlm.nih.gov/pubmed/13268678

Here's the money quote:

"Although the restricted obese mice hadless fat than their unrestricted obese siblings, they still maintained body fat concentrations 2-4 times as great as their lean siblings who received 1.3-2.7 times as much food."

I think this is one of the most impressive demonstrations of the fact that leptin actively regulates body fatness, and body fat level is not just a passive result of voluntary food intake/exercise.

It seems to me that the suppression of NEFA release should be MORE important following a LC meal than a mixed meal. The purpose of it is for the adipose tissue to do its proper buffering role in the way that liver/muscle do in response to dietary carb and protein. A high fat meal is going to release more NEFA directly into circulation as well.

I understand that the low carber is on a "fat burning" metabolism. But if I eat high carb and have a "glucose burning" metabolism, and I eat a bowl of honey sweetened oatmeal, my metabolic rate (ignoring minor TEF) doesn't change but my body works to push that glucose into my cells and out of circulation. If instead I'm an LC'er and I drink a large mug of heavy cream cocoa, my fat burning rate may be higher than my oatmeal-self but it's not going to change. It is in my body's interest that the surplus lipid get cleared stored in adipose tissue.

I don't think it matters as much in energy deficit where the person is burning through the NEFA. But at maintenance? Just as chronically elevated glucose leads to glycation (and we can measure that with HbA1c), chronically elevated NEFA would lead to higher ectopic lipid content. Would be nice to have a measure of that.

Stephan ... some thoughts re: leptin. Without putting words in your mouth, I think you would agree that the human species has not undergone some en masse genetic alteration that altered leptin signalling/receptors/etc. So that being the case, historically, there seemingly have always been obese humans and we can presume some of these genetic-variant obese may well have a leptin issue that causes the obesity.

But to me, for the vast majority of today's obese, whatever disruption in leptin seems to be the result of stuffing our fat sick rather than the cause. Leptin seems to be our "stop gap" regulator ... we just override it.

Fuel partitioning may well be leptin controlled as well, but as I asked a while back, when's the last time you saw a 130 lb obese person. Clearly folks carry weight differently. I'm roughly the same size as women who weigh 50 lbs less than me. Some can lose 20 lbs and go down two pants sizes, others barely find their current pants get noticeably looser. I get the impression you think I don't believe in any sort of homeostatic system. That's just not the case. I believe the vast majority of us are so disconnected from it -- due to not having to lift a finger for food for starters -- some conscious control is needed.

Anecdote from my research days. Put a normal Long Evans or Sprague Dawley rat in a cage with access unlimited chow and they will get fat eventually. Happened time and again when we would order up rats for a study and timing was off so they got too big for them. Such animals were used for control plasma, tissues, microsomal preps, etc. I've seen the fat upclose and personal ;-)

What was the chow made of (rethorical question)? If the critters get fat when fed ad libitum, the food is messing with their apetite regulation/energy homeostatis. I believe it’s not so much availability of energy which determines how much the rat (or human being) eats and gains, but the food in which it is delivered. Why don’t cows become obese when they are roaming in an environment with plenty of grass? Why will they eat too much and get obese (and sick) when you give them corn? Ever seen an overweight cat living om birds and mice? My aunt’s cat doesn’t get pet food, because it has an almost unlimited supply of prey around her farm. If the cat has eaten, no mouse in the world is able to arouse her (to the chragrin of my aunt). Why do some populations with plenty of directly available food never eat more than they spend? Why do I not eat more than I spend, even though I can buy the whole supermarket if I like? Because we count calories? Because we are deliberately controlling how much we put in our mouths? I can assure you, speaking for myself that is very much not the case.

I might eat too much and get fat though, when I start eating foods that eventually mess with my apetite regulation. Like my obese neighbour’s cat, which for years has been fed a concoction it would never have seen in it’s natural habitat.

I’m sorry for repeating myself, but it’s quite some ago I made this argument.

'Why don’t cows become obese when they are roaming in an environment with plenty of grass? Why will they eat too much and get obese (and sick) when you give them corn?'

I'm wondering about how cows eat. Don't they stand in grass, eat and then move on? Do they eat corn that way? How many calories are in the corn and how many calories are in the grass? This is fresh grass where they stand. If you put them in pens, where normally they would not be roaming, but standing and fed corn in large amounts to fatten them, could you feed them very large amounts of less-caloric dense grass to keep their caloric intake the same as when they were fed the corn?

Just trying to picture how cows would be fed grass from the field so that it would match the way they are fed corn.... so that the calories are the same.

Our cat was considered unadoptable by the people who showed her to me at the shelter. She was 4 or 5 times larger (that is, fatter - she looked like she had swallowed a cat) than the other cats. She'd been living in a cage there for a few years and they let her out at night, alone, to roam the small two rooms of the shelter. Needless to say, she was fed regularly, and they didn't put her on a diet; she ate the same dry cat food as all the other cats there.

Because she had some behavioral problems, she kept ending up back at the (no-kill) shelter. We adopted her anyway. Every time I look at her, I think of what my favorite fitness guys say: (paraphrasing)'It takes a lotta, lotta activity to undo the effects of overfeeding.' Nothing magnifies the effects of overfeeding like being confined and fed (note: we adopted her anyway, bad behavior and all...)

Sorry to say, she has NOT lost any weight. All cats that get adopted have to stay 'indoor cats' and, in addition, we had to promise that we would not have children, dogs, or other pets in the house. So she reigns over this household, fat as ever, despite having two flights of stairs in the house! Her behavioral problems: she 'playfully' scratches and bites.

@eulerandothersTo answer your question: Cows penned up (e.g. all winter (roughly Oct/Nov to March) in a feeding shed here in Ireland, and I imagine it is done similarly elsewhere in Europe) and fed hay (dried grass) and silage (fermented grass) don't get fat over the winter.

Cats ARE meant to be carnivores. I also propose that dry food is so far from a natural diet for cats it should be illegal to sell it! Even the dry food we used to get our cats that contained actual chicken protein or the like is just not what these animals should eat. We had two house kitties -- former feral strays -- and fed them dry b/c it was convenient. They got fat. I will never feed a cat dry food again, period. I switched them to wet almost no carb gluten-free food. Both lost weight. One died in his sleep. The other is quite a bit thinner now but still not thin. No house cat is as active as a cat in the wild, and even outdoor cats know where to come and when for their food. I've known plenty of cats to get fat. On their own hunted food? No ... that's one point.

Even given their natural foods, wild animals can fatten. Talk to my bird-feed seed thief squirrels.

Melchior, this does show that the wrong diet in unlimited supply is the problem. Rats, like humans, are suckers for CAF. We humans do have the wherewithall, however, NOT to eat crap food.

I am visiting a cat now (owner is ill) and feeding him wet cat food every day. He is thinner than my cat. He's an old cat and his teeth are in bad shape. He's been eating wet cat food for the last 10 years, at least. I don't think he's ready for dentures, but he's definitely ready for a breath mint.

Yeah, I tend to think a cat in the wild eats bones that help with that sort of thing. For my kitty it's an allergy thing - at least in part. Switching to wet, mostly fish with maybe a little rice in it has helped his allergies tremendously. I used to get him the cat tuna (that's it!) from Trader's but he doesn't seem to like it since his brother died :( When these guys were young they used to like to chew on the dried pig ears like you get for dogs. Wish we had kept that up b/c I think it would help, but he wants nothing to do with that now.

In an ideal world pet cats would roam free. We never could let these two out of the house for various reasons, not the least of which I didn't want my kitty to become road kill or coyote food.

Hi Jay, I used to live in beef cattle country and yes, many were being fed hay. But as even Eades described on his recent Mangalista kill post given the option of roaming for food or chowing at a trough, these animals seem not much different than us humans. A cow has to roam and graze quite a ways to get the same calories as some corn from a trough.

There is a good issue here aside from calories and availability -- it is any animal (humans included) eating a diet for which they are not well suited. Clearly humans are not best served by pizza, ice cream, fast food burgers and fruit loops.

I also plan to address other issues of obesity and eating disorders in greater detail in the coming months. I had mostly confined such things to the personal blog, but there seems to be an ignorance (not using that in a derogatory way) of ED's in the more academic discussions on obesity (becoming so and/or reversal of the condition). As someone who has been there I hope to inject this more into the conversation as in many cases it is likely FAR more dominant a factor than any macronutrient or hormone or anything.

I agree of course that genetic problems with leptin signaling aren't the cause of common obesity. However, I don't think the homeostatic system has been overridden in obesity. All signs suggest that the system is still functioning, but at a higher level. If it had been overridden and the body was above its "setpoint" or whatever you want to call it, the body of an obese person would not oppose a decrease in fat mass (by mounting a homeostatic response), and it clearly does. That's why I think environmental factors (diet/lifestyle) have actually increased the defended level of fat mass.

It's true that certain rodent strains will eventually gain fat on chow (although it's not that common that one will become frankly obese in my experience). But keep in mind, they're typically being kept in a cage where exercise is impossible and the only thing to do is eat. Exercise maintains leptin sensitivity. If you put a wheel in the cage and allow voluntary exercise, they gain less fat over time on both chow and obesogenic diets. Voluntary exercise is part of the "energy out" part of the homeostasis mechanism and it's usually almost completely cut off in standard research rodent housing.

Intuitively, I think there's a lot of merit to the setpoint theory. As I mentioned in other comments, it seems to work for wild animals and genetically-predisposed lean men. You artificially fatten them, they revert back to normal weight.

But, I believe that in probably 90% of the obese, this setpoint was long ago overridden. For example, I am not genetically predisposed towards obesity. My father -- whom I take after in outward characteristics down to my fingernails -- is lean and I probably would be too were it not for what I did to myself.

So as an athletic/active kid through my early teens Mom fed me a diet not all that unlike your own. I did, however, get junk through barter at school and my granny fix. Then in HS I had a little money and opportunity and had lunch at BK a few more times than needed. I slowly packed on a few pounds. Why didn't my setpoint stop this? I wasn't gorging. Near as I can figure your answer will be related to the palatability/food reward. But I guess what I'm asking is for you to confirm or clarify your thoughts on this with what I'm proposing they might be for my situation.

OK so after a year or so of this and going through puberty (a bit later than most) my setpoint was "reset" up about 20 lbs? Then what? My body was defending that when I put myself on a rather severe CRD and lost 30 lbs or so? This might explain why I started binging as my body sent out uncontrollable hunger signals?

That seems fair enough, but what happened next? For around 18 months I managed to maintain my new lower weight. Why didn't my body reset that setpoint at least back to where it had been? But then I definitely overrode any signals any body might be sending and binged horribly up around 50 lbs in a semester of college. This would have been overfeeding any study would have been proud of!

Why, when I "sobered up" come May and decided to take it off was it so difficult? Why did not my body just naturally revert to the lighter weight?

The yo-yo's continued for the next 15 or so years always topping off at around the 200-210 mark and now bottoming out at around 145-150 (10 or so pounds higher than my pre-dieting puberty/BK weight).

How does setpoint explain someone like me if not for the fact that humans routinely override innate homeostasis? We are the only species I know of who dances around a fire roasting a pig. Well, my cats have been known to bat around a mouse for a while before killing it, but I think you get my drift.

It seems to me with fat, once our bodies "own" it, they lose sight of how much we actualy have. And they defend against losing a certain amount of fat for a certain period of time. In this regard, there may be some merit to trying to lose weight for a period followed by just holding ground, allowing the body to sense a caloric balance and come out of "starvation mode" before making another push.

I would very much like to know the answers to these questions too! The bland, boring diet for controlling weight is interesting, but I think there may be more to it than that. I was bored out of my mind with the food I was eating on VLC, but it was all I could do to maintain my weight about 20 pounds above my goal. It could be the bland diet as recommended by Stephan (as I understand it) is both low in sugar and somewhat low in fat, and that may be the key. From some studies I've read calories from both sugar and fat seem to be relatively "invisible" to the body. According to this paper (sorry no full text) both high fat and high sugar snacks do not seem to prevent people from eating just as much as they would have without the snacks. I really wish they had another group eating something like a starch snack or maybe even a protein snack group, but they didn't. Anyway, I'm still trying to figure this out too.

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